Natural killer (NK) cells are essential mediators of host defence, survival and reproduction. They provide early defence against infection, determine when adaptive immunity is needed, facilitate implantation in pregnancy and kill tumors. To perform these functions NK cells use many receptors, most being differentially expressed to create diversity within NK cell populations. In human and mouse there is striking divergence in the types of NK cell receptor, but a common theme is the engagement of MHC class I or class I-like ligands. The more divergent receptors are also highly polymorphic within mouse and human populations, and particular variants have been associated with resistance to infection. In short there appears to be strong diversifying selection upon the NK cell response, consistent with its role in innate immunity and its potential for terminating infection before incapacitating disease develops. Phylogenetically, humans and mice are quite closely related, indicating that much of the global diversity in NK cell receptor biology remains undiscovered. To determine the overall scope of NK cell receptor diversity we propose to study selected species that represent the phylogenetic range of mammals: the class of species whose defence systems and mode of reproduction are most similar to those of humans. We propose three complementary specific aims that will determine the presence and nature of four types of NK cell receptors in the targeted species: the natural cytotoxicity receptors, the lectin-like receptors encoded by the natural killer complex (NKC), the immunoglobulin-like receptors encoded by the leukocyte receptor complex (LRC) and novel receptors not discovered in the study of humans or mice. Aim 1 will focus on characterization of cDNA from peripheral blood mononuclear cells, Aim 2 will focus on genes whose expression evaded cDNA analysis, and Aim 3 will focus on genomic organisation of the gene families encoding variable receptors. Rigorous phylogenetic analysis will be used to examine the evolutionary dynamics of individual genes, gene families and entire classes of receptor protein. An accurate phylogenetic history for the NK cell receptor families will be established. Consequently, this investigation will place the seemingly discordant results from humans and mice in their more proper biological context. Understanding how other mammals successfully face infection armed with different NK cell receptors should stimulate development of new strategies and innovative therapies against human infections, particularly zoonoses emerging from other mammalian species.